PROJECT SUMMARY The blood-brain barrier (BBB) serves as the major hindrance to efficient transport of life-saving therapeutics to the brain. Image-guided focused ultrasound can disrupt the BBB, but only temporarily and for a short period of time. Local implantation of drug-eluting depots is another option, but these are single-use systems that cannot be refilled or reused after implantation at inaccessible sites, limiting their clinical utility. Recently, we introduced click-modified refillable drug depots: injectable depots that capture prodrug refills from systemic circulation and release active drugs locally in a sustained manner. Capture of systemically-administered refills serves as an efficient and non-toxic method to repeatedly refill depots. Refillable depots in combination with prodrug refills achieve sustained release at tumor sites to improve cancer therapy while eliminating systemic side effects. Refillable depots have been successful in subcutaneous models of tumor recurrence, preventing tumor growth while eliminating systemic side effects. Unfortunately, the prodrug refills do not cross the BBB and thus refillable depots cannot be used alone in brain diseases such as stroke, degenerative disorders and brain cancers. We now propose refilling intracranial drug depots through the combination of non-toxic therapeutic prodrugs and image-guided transient disruption of the blood brain barrier. BBB disruption with focused- ultrasound provide a transient (~1 hour) window for the refilling of intracranial depots. The use of nontoxic prodrug refills allows us to administer large doses to maximally exploit the short window for drug delivery, allowing weeks and potentially months worth of therapeutic to be given in the short time window. After BBB reformation, the intracranial depots will release active drugs for a long period of time before being non-invasively refilled again. We further propose testing this innovative drug-delivery strategy in a patient-derived orthotopic GBM tumor model. This innovative combination of these two promising new technologies provides an approach to present therapeutic agents over a long period of time directly to the brain. Our efforts will further develop this promising approach, optimize parameters, and validate efficacy in preclinical studies. Clinical applications include the local release of chemotherapeutics, biologics and immunotherapy agents against GBM and other brain cancers, and administration of regenerative and immunosuppressive agents after stroke. If successful, the improvements made to this very innovative drug delivery strategy could open the pathway to clinical translation of refillable drug delivery technology.